Abstract. Breast cancer rates in American women of African ancestry (AA) continue to rise and the gap in mortality between AAs and women of European ancestry (EA) persists, the reasons for which are largely unknown. Investigating the hypothesis that evolutionary adaptation to endemic infectious diseases in Africa, such as malaria, resulted in more robust immune responses, but potentially more aggressive breast cancers with poorer prognoses, we found striking ancestral differences in distributions of SNPs in immune pathways, and in circulating cytokines and systemic immune response. Extending our research to local immune response in the tumor microenvironment (TME), we found a stronger presence of tumor infiltrating lymphocytes (TILs) in breast tumors from AAs than in EAs. Because TILs are typically associated with better survival, but AAs have poorer prognosis, in a pilot study, we investigated if various immune cell subtypes in tumor tissues differed in EAs and AAs. We found an important shift in gene expression profiles for TIL composition and the balance of immune responses, including a higher ratio of exhausted CD8 to total CD8 T cells in AAs, which was an independent prognostic factor in survival analysis. These preliminary findings have led us to hypothesize that the robust nature of the immune response in AAs is important for reshaping the biology of breast tumors, ultimately leading to the emergence of a more immune-resistant or refractory malignant phenotype. To address our hypotheses, we will take a multi-pronged approach built upon the established Women?s Circle of Health Study (WCHS) to resume enrollment of EA cases and continue recruitment of AAs, so that we will have ample statistical power to compare and investigate immune profiles in tumors from AA and EA women. We will first profile and compare breast TMEs using transcriptomic profiling in 250 AA vs. 250 EA patients, followed by validation of top markers and spatial characterization using Vectra multiplex immunofluorescence assay in tumors from 1,500 AA vs. 716 EA patients, with consideration of other molecular characteristics that differ between groups. We will examine relationships between immune phenotypes and breast cancer survival, as well as inflammation-related epidemiologic and social factors that may vary between EAs and AAs, or are differentially associated with risk by ER status, to investigate why breast tumor immune response would differ by race. To complement this research, we will employ comprehensive phenotypic and functional assays to determine the inherent response of immune cells from AA vs. EA cancer patients relative to healthy controls. Our study will provide evidence at both immune marker and functional levels that breast tumors from AA women have a stronger immune cell repertoire, but the balance of their TME is shifted towards an unfavorable dysfunctional state. Our findings may inform clinical investigations of immunotherapy focusing on breast cancer in AA women, and may guide the way for immunotherapy to activate exhausted T cells, ensuring that all groups of patients will receive equal benefits from cancer immunotherapy.